Caloric restriction (CR) without malnutrition has been consistently shown to increase longevity in a number of animal models, including yeast, C. elegans, and mice. However, the effect of CR on the lifespan of non-human primates remains controversial, and may be heavily influenced by dietary composition. The lifespan extension associated with CR in model organisms is believed to operate through its effects on GH, GHR, leading to subsequent deficiencies in IGF-1 and insulin levels and signaling. The effect of the insulin/IGF-1 pathway on longevity was discovered in C. elegans, by showing that mutations in this pathway, regulated by nutrient availability, caused a two-fold increase in lifespan. Other studies revealed that mutations in orthologs of genes functioning in growth signaling pathways, including Tor-S6K and Ras-cAMP-PKA, promoted aging in multiple model organisms, thus providing evidence for the conserved regulation of aging by pro-growth nutrient signaling genes.
Recently, it has been shown that humans with growth hormone receptor deficiency (GHRD), exhibiting major deficiencies in serum IGF-1 and insulin levels, displayed no cancer mortality, nor diabetes, and despite having a higher prevalence of obesity, combined deaths from cardiac disease and stroke in this group were similar to those in their relatives. Similar protection from cancer was also reported in a study that surveyed 230 GHRDs.
Protein restriction or restriction of particular amino acids, such as methionine and tryptophan, may explain part of the effects of calorie restriction on longevity and disease risk, since protein restriction reduces IGF-1 levels, can increase longevity in mammals independently of calorie intake, and has also been shown to reduce cancer incidence in rodent models.
Accordingly, there is a need for dietary interventions that can alleviate symptoms of age-related illness in both subjects willing to chronically modify their diet and those that would only consider periodic interventions but otherwise continue their normal diet.